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Chapter 3: Rationality of Drugs  
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Annexure 4

Irrational Combinations of Paracetamol1

Since paracetamol is a very commonly used drug, we briefly discuss here the rationality of formulations available which contain paracetamol.

1. Combined formulations of paracetamol with NSAIDS

Combination of paracetamol with any NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) can be justified on the basis that NSAIDs possess anti-inflammatory activity which is lacking in paracetamol. However, anti-inflammatory activity is required in inflammatory conditions like various types of arthritis. In such cases anti-inflammatory property itself relieves the pain, so, paracetamol has no role and combination is irrational. Furthermore, NSAIDs like phenylbutazone are banned and so is the combination. On the other hand NSAIDs like ibuprofen and indomethacin also possess antipyretic property thus no additional benefit occurs when such combination are used. Moreover, combinations of NSAIDs are more likely to produce nephropathy as compared to single agent.

2. Combined formulations of paracetamol with analgesics

Paracetamol itself is an analgesic. So combination with other analgesics is irrational. Such combinations have not been proved superior to either of the drugs except when paracetamol combined with an opioid like codeine or dextropropoxyhphene. However merit of paracetamol + dextropropoxyphene combination is controversial. Clinical trials have been inconclusive as to whether it has efficacy superior to either drug alone. Popularity of this formulation may be due to mild euphoric effect of dextropropoxyphene. The main disadvantage is that in cases of overdose death may occur within an hour due to the rapid absorption of dextropropoxyphene leading to respiratory depression.

3. Paracetamol combination with central muscle relaxants

Formulations containing paracetamol with four central muscle relaxants are available. Central muscle relaxants were previously indicated for spastic condition and are still prescribed but their use is declining owing to their doubtful value. These relaxants have not been included in the latest issue of Goodman and Gilmann's Pharmacological Basis of Therapeutics (1996 edition). If muscle relaxants are useful even then paracetamol does not provide any benefit if combined with these agents.

4. Formulations of paracetamol with antihistaminics and nasal decongestants

Various irrational formulations are available as cough and cold remedies containing antihistaminics, mucolytics, nasal decongestants and cough suppressants. These formulations are useless. In most such formulations paracetamol is one of the ingredients which is irrational.

5. Combination of paracetamol with various other drugs

(a) Dicyclomine: Dicyclomine is an antispasmodic useful for colicky pain. Combination of paracetamol does not produce any advantage but cost of the treatment is increased. Paracetamol is not useful in colicky pain.

(b) Orphenadrine: Orphenadrine is a drug for Parkinson's disease as it possesses potent central anticholinergic property. Additionally it is also a central muscle relaxant but this property is of doubtful utility. There is no justification of combining paracetamol with orphenadrine as paracetamol does not produce any beneficial effect in Parkinson's disease.

(c) Disodium hydrogen phosphate: Although only one preparation is available but without any benefit as disodium hydrogen phosphate is an alkalinizer. Here probably it is used as a diaphoretic (increases sweat) but paracetamol alone is useful if there is fever and in such cases it should be administered separately as and when required.

(d) Ergotamine: Paracetamol with ergotamine has some justification. Ergotamine is used for acute attack of migraine, addition of paracetamol products better effect as compared to ergotamine alone, so, this formulation is rational to some extent, but not necessary.

(e) Metoclopramide: This formulation is also rational to some extent due to the fact that metoclopramide increases the speed of absorption of paracetamol. Moreover, when this formulation is used for migraine attack, paracetamol provides some relief, and metoclopramide apart from increasing the absorption of paracetamol, corrects gastric disturbances in migraine (nausea, vomiting and slight degree of gastral paralysis).

In general, fixed dose formulations or combinations should not be prescribed unless there is good reason to consider that patient needs all the drugs in the formulation and that the doses are appropriate and do not need to be adjusted separately. Similarly fixed dose formulations containing paracetamol should not be prescribed without good reason.

It can be concluded that paracetamol should preferably be prescribed separately whenever required as it provides symptomatic relief in mild to moderate somatic pain and in cases of fever, which is a symptom of various diseases, particularly infections. Paracetamol should not be used as a sleep(ing) companion.

     
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